One of the symptoms of schizophrenia is a decrease in the capacity to filter and process novel sensory or cognitive stimuli. This can be demonstrated in both animals and humans by using a paradigm called prepulse inhibition (PPI). If an intense, sudden stimulus is presented, it elicits a startle response, which can be monitored in animals by measuring the flinching of the animal. If the startling stimulus is preceded by a weak prepulse, then the startle response is inhibited. schizophrenia patients show a deficient or weak PPI, reflecting a lack of inhibitory function or sensorimotor gating (Braff et al Arch. Gen. Phychiatry 1990; 47(2) PP 181–8). Prepulse inhibition in animals has been used as a model for screening drugs to treat schizophrenia. If the phenotype of a weak PPI can be reversed in an animal model by a drug, then it is indicative that the drug could be used to treat schizophrenia. However, no models currently exist wherein PPI develops naturally as the animal matures. Current models are generated by inducing the phenotype either by external stimuli, for example pre or post-weaning social isolation, or chemically by compounds such as apomorphine or quinpirole. A neurodevelopmental model that naturally develops some of the symptoms of schizophrenia such as PPI would provide an extremely useful tool for screening compounds to treat schizophrenia. Such a model, as presented herein, provides advantages over the prior art in that it mimics the natural development of schizophrenia, rather than having to be artificially induced.
Endothelial differentiation gene 2 (EDG2) has enriched embryonic expression in the developing cerebral cortex and dorsal olfactory bulb, and postnatal expression in myelinating glia including Schwann cells and other oligodendrocytes. It is a lysophosphatidic acid receptor, and has been shown to couple to at least two different G-proteins: Gi/o and a pertussis toxin insenstive G protein that appears to be G12 or G13. (Fukushima and Chun, Prostaglandins & other Lipid Mediators (2001) 64 pp21–32). However, no role has been postulated for EDG2 in schizophrenia. The present inventors have surprisingly managed to develop a developmental model for schizophrenia by a targeted knockout of the EDG2 gene.